Project Summary The overall focus of this Virtual Consortium project is on neuroinflammation and the neuro-immune axis as a critical link between viral infection and susceptibility to injury from environmental neurotoxins. Neuroinflammatory activation of glial cells may represent an important causal link in the `two-hit' theory of neurological disease, sensitizing susceptible brain regions to damage from distinct environmental stressors and thereby promoting the onset of clinical disease. The proposed Virtual Consortium will examine how infection with commonly encountered RNA viruses, including Western Equine Encephalitis virus (WEEV) and H1N1 influenza virus, the current worldwide pandemic flu virus, influences the severity of neurological outcomes following exposure to neurotoxic metals and pesticides. Neuroinflammatory mechanisms examined in animal models will be compared to advanced PET imaging of neuroinflammation in individuals occupationally exposed to manganese (Mn) in conjunction with an analysis of their history of viral exposure. This Virtual Consortium will examine signaling mechanisms in microglia and astrocytes that regulate neuroinflammatory injury following exposure to viruses and selected environmental neurotoxins using both transgenic mouse models as well as clinical imaging in Mn- exposed patients. The Consortium will bring together collaborators in neurovirology and neurodegeneration (Richard Smeyne, Thomas Jefferson University), neurology and clinical imaging (Brad Racette, Washington University, St. Louis) and neuroinflammation (Ronald Tjalkens, Colorado State University) to identify key neuroinflammatory mechanisms modulating the response to infectious and neurotoxic environmental exposures that could increase the risk of developing neurodegenerative disease. It is our central hypothesis that encephalitic viral infection causes a persistent inflammatory phenotype in microglia and astrocytes that enhances susceptibility to neurotoxic injury. This hypothesis will be tested by the following interconnected Specific Aims: Specific Aim 1 (Tjalkens, Colorado State University) - Identify inflammatory signaling pathways in microglia modulated by Western Equine Encephalitis Virus (WEEV) that promote glial activation and neuronal injury from manganese and rotenone; Specific Aim 2 (Smeyne, Thomas Jefferson University) - Determine mechanisms by which H1N1 influenza virus alters the effects of manganese and rotenone on neuronal injury; Specific Aim 3 (Racette, Washington University School of Medicine) - Characterize patterns of neurological dysfunction and microglial activation in manganese (Mn) exposed workers. We expect that this Virtual Consortium will have a significant impact on our understanding of interactions between environmental neurotoxins and viruses that can promote neurological disease, which are currently only poorly understood. Such interactions are likely to have enormous implications to public health, given the widespread incidence of both viral infections and exposure to neurotoxic agents in the general population. The proposed ViCTER consortium addresses this problem with an interdisciplinary approach integrating powerful basic research models with advanced PET neuroimaging in a patient population occupationally exposed to Mn that will be examined for a history of viral infections. The outcomes from these studies are very likely to inform better policy decisions regarding identification and prevention of environmental risk factors for neurodegenerative disease.